JOHN ZUBIALDE, MD

PROFESSOR OF FAMILY AND PREVENTIVE MEDICINE

UNIVERSITY OF OKLAHOMA COLLEGE OF MEDICINE

Celiac Disease: Myths and Reality

Objectives:

Participants will:Understand etiology of Celiac DiseaseUnderstand the spectrum of disease

manifestationBe able to appropriately test for the diseaseBe able to appropriately treat and monitor

patients with the diseaseBe able to identify and monitor for associated

conditions

History and Pathogenesis First described by Aretaeus of Cappadocia in 100 AD

Cause unknown until WW2 when Dutch Pediatrician Willem Dicke described the association of relapsing diarrhea in children with consumption of bread and cereals and its resolution with their removal. Wheat, barley, and rye noted to be primary offending agents.

In 1954 the pathogenic lesion of small bowel including mucosal inflammation, crypt hyperplasia and villous atrophy was described in children with malabsorption

In 1980’s this “disease of childhood” recognized as being the same disease as “Nontropical Sprue” in adults. (Gluten Sensitive Enteropathy or Nontropical Sprue)

1990’s on -we now understand it as an autoimmune disease with clear genetic associations and a typical antibody signature. It has links to other autoimmune diseases.

Ramifications of non-treatment are only now being understood.

Pathogenesis

Genetic Association In genetically predisposed individuals, it is an immune

disorder triggered by an environmental agent (alpha gliadin component of gluten) which is only partially degraded by tissue transglutaminase. HLA DQ2 and or DQ8 gene loci. Only 36% of disease is HLA component dependant – so other associated genetic foci must also be in play.

Associated Autoantibodies IgA autoantibodies to endomesium (smooth muscle

connective tissue) and more specifically to tissue transglutaminase which functions to deamidate gliadin peptides.

IgG autoantibodies to deamidated gluten peptides (eg gliadin)

Pathogenesis

Incompletely understood Gliadin Reactive T Cells

Incomplete degradation of gliadin peptides by tissue transglutaminase- stimulation of T cells with associated T Cell activity on targeted intestinal and other tissues

Innate Immunity: Response by macrophages, monocytes and dendritidic cells

Humoral- Leukocyte associated activity Gliadin receptors on intestinal epithelial cells that

transport gliadin peptides to the lamina propria for T cell activation.

Reality or Myth?

Celiac disease is relatively rare in our population

“Classic” Celiac disease with its associated diarrhea and malabsorption is the most common presentation

Cultural prevalence changes with diets

Epidemiology

Highest known prevalence: Whites of Northern European Ancestry Reported prevalence in 1950’s- 1:4000 to 1:8000 based on classic

presentation of malabsorption Epidemiological studies based on biopsy 1:300 – 1:500 Epidemiological studies based on genetics and auto-antibodies 1:100-

1:250 At risk groups: 1:22 first degree relatives, 1:39 second degree

relatives High prevalence- suggests that “silent celiacs” are much higher

percentage than “classics” Increasing prevalence with age and exposure to high wheat “western

diets” in transplants from other cultures. Small absolute increase in Mortality compared with general

population Small increase in digestive tract cancers

Reality or Myth?

Celiac disease is exclusively a disease of the gastrointestinal tract.

Types: Five Current Classifications

Classic Disease: Severe GI symptoms: Malabsorption with steatorrhea, weight loss, vitamin and nutrient

deficiency that resolves on a gluten free diet within weeks to months Severity of symptoms does not fully correlate with histological changes seen on biopsy

(villous atrophy) Decreasing severity of villous atrophy from proximal to distal small bowel

Atypical Disease: Antibody Positive: with and without villous atrophy

Mild to Moderate GI complaints Other associated conditions

unexplained iron deficiency anemia dental enamel defects unexplained arthritis and myalgias unexplained transaminase elevations infertility (both male and female) unexplained neuropathies, headaches (migraine), ataxias, or epilepsy neuropsychiatric including general sx of fatigue, slow mentation, and depression/dysthymia metabolic bone disease and osteopenia/osteoporosis (vitamin D deficiency)

Antibody Negative: Irritable Bowel Disease that responds to gluten free diet

Types (continued)

Asymptomatic or “silent” disease: Have villous atrophy and auto-antibody evidence No GI symptoms No associated conditions

Latent Disease: “Disease in remission” Clinical improvements and loss of

clinical and histological findings after gluten free diet is implemented. Symptomatic disease may seemingly remit even after later returning to a glutinous diet.

Potential Disease: Positive antibody testing

No GI symptoms No villous atrophy and or associated symptoms.

Associated Conditions

Dermatitis Herpetiformis Type 1 Diabetes Mellitus Selective IGA deficiency- makes diagnosis more complicated Down Syndrome Unexplained Liver Disease- unexplained enzyme elevations GERD with associated motility issues Eosinophilic esophagitis Atrophic Glossitis: “burning tongue” Inflammatory and Irritable Bowel Disease Reproductive: Increased miscarriage, infertility, and IUGR babies. Myocarditis and idiopathic dilated cardiomyopathy Pancreatitis Autoimmune thyroid disease

Reality or Myth?

Screening for Celiac Disease should be a regular part of health screening.

Diagnosis

Who should be tested? GI sx

Chronic or recurring diarrhea Malabsorption and weight loss Abdominal bloating, immotility, and chronic irritable bowel

Other associated sx/findings Unexplained Iron, B12, folate deficiency Persistent elevation of serum aminotransferases Recurrent apthous stomatitis, dental enamel hypoplasia, sore tongue Idiopathic onset of periferal neuropathy, migraines, and irritable bowel. Men with idiopathic infertility Women with infertility, recurrent fetal losses, idiopathic low birthweight infants

High risk 1st and second degree relatives of celiacs Dermatitis Hepetiformis Type 1 diabetes Other autoimmune diseases Autism (?) Turner, Downs, and Williams syndromes

Testing

Serologic studies should be done on a glutenous diet – age 5 and over Serum IgA IgA tissue transglutaminase (sn 98 sp 100) IgA endomesial antibody (sn 98 sp 98) Antigliadin antibody -no longer used- low sensitivity and specificity (sn 80

sp 95) IgG to Deamidated Gliadin Peptide (DGP)

The only reliable test in IgA deficient individuals Strong assn with other food antibodies (casein, ovalbumin,lactoglobulin)

Small Bowel Biopsy – Gold Standard Recommendation for those with positive serologic testing – under debate Duodenal bulb and 2nd and 3rd portion of the duodenum

Genetic HLA DQ2 and DQ8

Reality or Myth?

All antibody positive patients should be treated

Treatment

All Individuals with Biopsy proven disease All Individuals with Atypical Disease: Antibody presence and

symptoms/findings- even minor Individuals with antibody presence, no sx, no villous atrophy-

debatable Individuals with Atypical Disease variant: Irritable Bowel –antibody

negative- Well worth a try- but this is a hard diet in western culture. DIET, DIET, DIET

Gluten Free Diet – Wheat, Rye, and Barley –Definitely Read labels carefully- many stabilizers and additives contain gluten (malt extracts

etc) (eg Soy sauce) Avoid dairy if pt is in symptomatic phase Oats – more complex- Oats contain a related gluten and this may be “dose

dependant” American Oat supply is frequently cross contaminated with wheat – know your oat

supplier/manufacturer

Treatment

Micronutrient deficiencies should be treated Iron Folic acid, Vitamin D B12

Be careful of bone mass in children and adults

Vaccination Pneumococcal vaccination recommended, especially

in IgA deficiency.

Take Home

Celiac Disease- Knowledge about this disease is evolving rapidly

It is an autoimmune diseaseBetter characterized as “Gluten Sensitive

Enteropathy” (Gluten + Genetics+ Environment)

It is a “Spectrum of Disease” that is complex and associated with multiple presentations and tissue targets based on a multitude of genetic and environmental factors.